Many cells undergo programmed cell death, or apoptosis, during fetal development. Apoptosis also may occur when a cell becomes damaged or deregulated, as is the case during tumour development and other pathological processes. Thus, when functioning properly, the body can induce apoptosis to rid itself of cancer cells.

Not all cancer cells succumb in that manner, however. Some find ways to escape apoptosis. Two mutations identified in human tumours lead to a loss of programmed cell death. One mutation inactivates the p53gene, which normally can trigger apoptosis. The second mutation affects a proto-oncogene called BCL-2, which codes for a protein that blocks cell suicide. When mutated, the BCL-2 gene produces excessive amounts of the BCL-2 protein, which prevents the apoptosis program from being activated. Malignant lymphomas that stem from B lymphocytes exhibit this BCL-2 behaviour. The alteration of the BCL-2 gene is caused by a chromosomal translocation that keeps the gene in a permanent “on” position. Loss of p53 function protects cells from only certain kinds of suicide, whereas the BCL-2 alteration completely blocks access to apoptosis.

The blocking of apoptosis is thought to be an important mechanism in tumour generation. That mutation also may contribute to the development of tumours that are resistant to radiation and drug therapies, most of which destroy cancer cells by inducing apoptosis in them. If some cells within a tumour are unable to commit suicide, they will survive treatment and proliferate, creating a tumour refractory to therapy of this type. In this way apoptosis-inducing therapies may actually select for cancer cells resistant to apoptosis.

Immortalization is another way that cells escape death. Normal cells have a limited capacity to replicate, and so they age and die. The processes of aging and dying are regulated in part by telomeres, which, once reduced to a certain size through repeated cell divisions, cause the cell to reach a crisis point. The cell is then prevented from dividing further and dies.

That form of growth control appears to be inactivated by oncogenic expression or tumour suppression activity. In cells undergoing malignant transformation, telomeres do shorten, but, as the crisis point nears, a formerly quiescent enzyme called telomerase becomes activated. This enzyme prevents the telomeres from shortening further and thereby prolongs the life of the cell.

Most malignant tumours—including breast, colon, prostate, and ovarian cancers—exhibit telomerase activity, and the more advanced the cancer, the greater the frequency of detectable telomerase in independent samples. If cell immortality contributes to the growth of most cancers, telomerase would appear to be an attractive target for therapy.

In normal tissues, the numbers of cells are carefully regulated, and the constant replenishment of cells is left to a specialized cell called the tissue stem cell. A property of tissue stem cells is that they divide infrequently, and when they divide, one daughter is a stem cell and the other daughter differentiates and replicates several times, giving rise to differentiated progeny. This division of labour—preserving the replicative potential (stem cell) and carrying out the specific functions of the organ (differentiated cells)—is mimicked in tumours, but in a less-organized fashion.

Cancer stem cells have been unequivocally identified in some tumour systems and are important because if they are not eradicated, no matter how many tumour cells are killed by therapy, the tumour will come back. Whereas the “stemness” of a cell in normal tissues is a stable characteristic, there is evidence that in cancer, stemness is less permanent and can be acquired or shed by proliferative tumour cells.

Histopathologists long observed that when epithelial cells from a cancer invade surrounding membranes, effecting their escape from the tumour site, they often become elongated or spindly. Molecules known as E-cadherin, which changes cell-to-cell adhesion in epithelium, and N-cadherin, which favours cell migration, have been found to be under expressed and overexpressed in invading cancer cells. In addition, a series of important control circuits that operate at the cellular level during the normal development of the embryo and in wound healing are exploited by tumour cells to implement a program of invasion and distant spread. This so-called “epithelial-mesenchymal transition program” relies on a number of powerful transcription factors, which are stimulated by factors in the tumour cell environment and are capable of regulating the expression of the molecules that drive invasion and metastasis. Nontumour stromal cells (a type of connective tissue cell) can also stimulate the expression of those factors, and they are in part responsible for invasion at the edge of the tumour cell mass, the zone where tumour cells and host stroma interact extensively. In some instances inflammatory cells of the host immune system play a similar role in facilitating invasion.

For metastatic cancer cells to be clinically significant, they must grow and cause symptoms at the site that they have colonized. Single tumour cells from a distant tumour can be found in a patient’s bone marrow, yet they may never proliferate and cause problems. To grow as a distant deposit, cells need to find suitable “soil” conditions in the target organ, such as the presence of growth-stimulating signals. In contrast, deprivation of nutrients or growth suppression by immune cells may keep colonies of tumour cells dormant for significant lengths of time.

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